Patient‐reported outcome measures in birch pollen allergic patients treated with sublingual immunotherapy reflect real life
Authors: Farah Bahbah, Catherine Gentil, Bernardo Sousa‐Pinto, G. Walter Canonica, Philippe Devillier, Oliver Pfaar, Jean Bousquet
Journal: Allergy (2022)

To the Editor, According to the National Institutes of Health, Patient-Reported Outcome Measures (PROMs) are "[…] measurement[s] based on a report that comes directly from the patient […] about the status of [his] health condition without interpretation […] by a clinician or anyone else" (https://toolkit.ncats.nih.gov/glossary/patient-reported-outcome/). The most frequent PROMs in allergen immunotherapy trials include total nasal symptom score (TNSS), total ocular symptom score (TOSS), total symptom score (TSS) and visual analogue scales (VASs). However, these PROMs have not been thoroughly compared with each other and with quality-of-life-related PROMs. In this study, we correlated TNSS, TOSS, TSS and VAS rhinoconjunctivitis symptoms (VAS-RS) as daily PROMs with the Rhinoconjunctivitis Quality-of-Life Questionnaire (RQLQ), used as a comparator.1 In addition, we assessed the correlation between VAS-RS and the remaining daily PROMs. We assessed data from a pivotal randomised, placebo-controlled sublingual drops immunotherapy trial with birch pollen2 (NCT01731249). Methods are fully described in the Supplement.3 For each patient, TNSS, TOSS, TSS and VAS-RS were assessed daily, and RQLQ weekly, from 2 weeks before to 2 weeks after the anticipated pollen season start date. TNSS assesses nasal symptoms, while TOSS assesses ocular symptoms. The TSS is calculated by adding TNSS and TOSS. We analysed data retrieved between the visit occurring at mid-pollen season and the visit occurring 2 weeks after the season. As RQLQ was measured once a week and the remaining PROMs daily, we performed different analyses, including: (i) only data from days when daily PROMs and RQLQ were simultaneously measured and (ii) weekly median data for each daily PROM. We analyzed data from 482 subjects, providing 2937 daily records (Table S1). The overall RQLQ was highly correlated with the same day VAS-RS (correlation coefficient adjusted for repeated measurements = 0.73; unadjusted Spearman correlation coefficient = 0.77) (Figure 1A,B) and with median VAS-RS collected during the week before RQLQ assessment (correlation coefficient adjusted for repeated measurements = 0.74) (Figure 1C). Correlations between the remaining PROMs and RQLQ or between VAS-RS and the other daily PROMs were also strong (Table 1; Figure S1). Similar results were obtained when considering the full pollen season or the seven worst days of the season (Tables S2 and S3). The strong correlation between VAS-RS with TSS4 and TNSS indicates the concurrent validity of VAS. The correlations between RQLQ and daily PROMs were similar when considering the last study day or the median weekly values. These findings are relevant since PROMs should reflect quality-of-life-related health status but suggest an overvaluation of recent symptoms when patients answer to the RQLQ (recall bias). The TOSS was less well correlated with RQLQ and VAS-RS.5 Although ocular symptoms are bothersome and affect RQLQ, RQLQ may not be optimal at reflecting ocular symptoms. Furthermore, the TOSS scale displays some limitations, as it only assesses two items (eye itching and tearing), displaying a lower contribution to TSS. The ranking order in correlations involving TSS, TNSS and TOSS was the same as that found for VASs on global, nasal and ocular symptoms in an independent real-world mHealth study using VAS work as a comparator6 (Table S4). Since VASs have already been assessed with real-world mHealth data, these results suggest that TSS, TNSS and TOSS reflect real-life data. In addition, a simplification of immunotherapy trial endpoints may be considered using VAS. This study has the limitation of solely concerning data from pollen season and from birch pollen allergy. Further studies assessing different periods and other allergies (namely to different pollens) are needed to assess the generalisability of the obtained results. Farah Bahbah and Catherine Gentil are members of Stallergènes. Dr. Devillier reports personal fees and non-financial support from Astra Zeneca, personal fees from Chiesi, personal fees and non-financial support from Boehringer Ingelheim, personal fees from GlaxoSmithKline, personal fees from Menarini, personal fees and non-financial support from Stallergenes, personal fees and non-financial support from ALK Abello, outside the submitted work. Dr. Bousquet reports personal fees from Cipla, Menarini, Mylan, Novartis, Purina, Sanofi-Aventis, Teva, Uriach, other from KYomed-Innov, other from Mask-air-SAS, outside the submitted work. Dr. Sousa-Pinto has nothing to disclose. Dr. Canonica has nothing to disclose. Dr. Pfaar reports grants and personal fees from ALK-Abelló, grants and personal fees from Allergopharma, grants and personal fees from Stallergenes Greer, grants and personal fees from HAL Allergy Holding B.V./HAL Allergie GmbH, grants and personal fees from Bencard Allergie GmbH/Allergy Therapeutics, grants and personal fees from Lofarma, grants from Biomay, grants from Circassia, grants and personal fees from ASIT Biotech Tools S.A., grants and personal fees from Laboratorios LETI/LETI Pharma, personal fees from MEDA Pharma/MYLAN, grants and personal fees from Anergis S.A., personal fees from Mobile Chamber Experts (a GA2LEN Partner), personal fees from Indoor Biotechnologies, grants and personal fees from GlaxoSmithKline, personal fees from Astellas Pharma Global, personal fees from EUFOREA, personal fees from ROXALL Medizin, personal fees from Novartis, personal fees from Sanofi-Aventis and Sanofi-Genzyme, personal fees from Med Update Europe GmbH, personal fees from Streamedup! GmbH, grants from Pohl-Boskamp, grants from Inmunotek S.L., personal fees from John Wiley and Sons, AS, personal fees from Paul-Martini-Stiftung (PMS), personal fees from Regeneron Pharmaceuticals Inc., personal fees from RG Aerztefortbildung, personal fees from Institut für Disease Management, personal fees from Springer GmbH, grants and personal fees from AstraZeneca, personal fees from IQVIA Commercial, personal fees from Ingress Health, personal fees from Wort&Bild Verlag, personal fees from Verlag ME, personal fees from Procter&Gamble, outside the submitted work; and member of EAACI Excom, member of ext. board of directors DGAKI; coordinator, main- or co-author of different position papers and guidelines in rhinology, allergology and allergen-immunotherapy. The authors would like to thank Anna Bedbrook for reviewing the English. 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